The objective of this project is to further develop a new progesterone formulation that is effective for hormone replacement therapy-protecting the coronary arteries against hyperreactivity. Such hyperreactivity results from the deficiency of progesterone after the cessation of ovarian function after menopause during the normal aging process. The anticipated new product will be further studied in monkeys in the catheterization laboratory and in human stress test electrocardiogram and echo cardiology protocols. These studies will determine the effectiveness of progesterone in extending treadmill stress test duration, echocardiographic cardiac wall motion, and lipid biochemical measures of coronary function. We will also explore the possible relationship of changes in blood lipids and platelet function. The new formulation is designed to be accepted sufficiently well by post- menopausal women to encourage compliance among those who initiate hormone replacement therapy-for a duration of decades in many cases. Protection of the cardiovascular system by progesterone can be expected to provide for a significant decrease in the incidence of cardiovascular disease during aging, and improved quality of life in post-menopausal women. The skin cream formulation is well accepted by women, has optimal pharmacokinetics for a once a day treatment, and is hypothesized to reduce cardiovascular risks, including coronary artery disease. Even though the risk of death due to cardiovascular causes is nearly 50% for post-menopausal women, and is far greater than any other risk, the presently available forms of hormone replacement therapy are used by only a fraction of those who would benefit. This leading risk of death and' available measures to minimize that risk are neither well understood nor readily accepted by post-menopausal women. This formulation has the potential to significantly improve that situation and enhance quality of life in post-menopausal women. PROPOSED COMMERCIAL APPLICATIONS: The percutaneous formulation of progesterone will produce a blood level to minimize the risk of cardiovascular disease, and thus may find widespread application in hormone replacement therapy. The number of people who would be potential consumers for the product consists of all postmenopausal women, a rapidly growing number which already exceeds 20 million.